Recently in the study of transcription factors associated with marker genes expression induction in adipocytes differentiation, peroxisome proliferator activated receptor (abbreviated as PPAR hereinafter), which is one of intranuclear receptors, has got attention. The cDNAs of PPAR were cloned from various kinds of animals, and plural isoform genes were found, particularly in mammals three types of isoforms (α, δ, γ) are known (see J Steroid Biochem. Molec. Biol., 51, 157 (1994); Gene Expression., 4, 281 (1995); Biochem Biophys. Res. Commun., 224, 431 (1996); Mol. Endocrinology., 6, 1634 (1992)). Further, it is known that PPAR γ isoform predominantly expresses in adipose tissues, immune cells, adrenal gland, spleen, small intestine, PPAR α isoform mainly expresses in adipose tissue, liver, retina, and PPAR δ isoform universally expresses without specificity for tissue (see Endocrinology., 137, 354 (1996)).
By the way, thiazolidine derivatives such as pioglitazone, ciglitazone, rosiglitazone, troglitazone etc. are known as agents for the treatment of non-insulin dependent diabetes mellitus (NIDDM) and are hypoglycemic agents which are used for the improvement of hyperglycemia in the patients suffering from diabetes. They are also effective for the improvement or correction of hyperinsulinemia, improvement of glucose tolerance and decrease of serum lipid and therefore they are thought to be considerably hopeful as agents for the improvement of insulin resistance.
In addition, one of the intracellular target proteins of these thiazolidine derivatives is exactly PPAR γ and it is resolved that they enhance the transcription activity of PPAR γ (see Endocrinology., 137, 4189 (1996); Cell., 83, 803 (1995); Cell., 83, 813 (1995); J. Biol. Chem., 270, 12953 (1995)). Therefore, a PPAR γ activator (agonist) which enhances its transcription activity is thought to be hopeful as a hypoglycemic agent and/or a hypolipidemic agent. Furthermore, since a PPAR γ agonist is known to promote the expression of PPAR γ protein itself (Genes & Development., 10, 974 (1996)), an agent which increases the expression of PPAR γ protein itself as well as PPAR γ activating agent is also thought to be clinically useful. Intracellular receptor, PPAR γ is related to adipocytes differentiation (see J. Biol. Chem., 272, 5637 (1997) and Cell., 83, 803 (1995)). It is known that thiazolidine derivatives which activate this receptor promote adipocytes differentiation. Recently it was reported that thiazolidine derivatives increase body fat and cause man to gain weight and to become obese (see Lancet., 349, 952 (1997)). From these, PPAR γ activators (agonists) and PPAR γ regulators for its expression that can increase the expression of the protein itself have hypoglycemic effect, hypolipidemic effect and are expected to be useful as agents for prevention and/or treatment of such as, glucose•lipid metabolic disorder (e.g. diabetes, hyperlipidemia (hypercholesterolemia, hypo-HDL (high-density lipoprotein)-cholesterolemia, hyper-LDL (low-density lipoprotein)-cholesterolemia, hypertriglyceridemia etc.), atherosclerosis, cardiovascular disease, hypertension, circulatory diseases etc.
Additionally, the fibrate compound (e.g., chlofibrate) is known as a hypolipidemic agent. It is also resolved that one of the intracellular target proteins of fibrate compounds is PPAR α (see Nature., 347, 645 (1990); J. Steroid Biochem. Molec. Biol., 51, 157 (1994); Biochemistry., 32, 5598 (1993)). From these facts, PPAR α regulators are thought to have a hypolipidemic effect, and so they are expected to be useful as agents for prevention and/or treatment of hyperlipidemia etc.
Besides, it has been recently reported that PPAR α possesses anti-obese activity (see WO97/36579). In addition, it was reported that the metabolic stimulation effect of lipid (cholesterol, HDL, LDL and triglyceride etc.) were induced by PPAR α agonists (see J. Lipid Res., 39, 17 (1998)). That is, it was reported that they had the elevating effect of high-density lipoprotein (HDL) cholesterol and the lowering effect of low-density lipoprotein (LDL) cholesterol, very low-density lipoprotein (VLDL) cholesterol and triglyceride. It was also reported that composition of fatty acids in blood, hypertension and insulin resistance were improved by administration of bezafibrate which is one of fibrate compounds (see Diabetes., 46, 348 (1997)). Therefore, since agonists that activate PPAR α and PPAR α regulators that promote expression of PPAR α protein itself have hypolipidemic effect, they are hopeful agents for the treatment and/or prevention of lipid metabolic disorder (e.g. hyperlipidemia (hypercholesterolemia, hypo-HDL-cholesterolemia, hyper-LDL-cholesterolemia, hypertriglyceridemia etc.), atherosclerosis, cardiovascular disease, adiposity, metabolic syndrome etc.), hypertension, circulatory diseases etc.
In contrast, PPAR δ is sometimes called PPAR β, or it is also called NUC1 in human. Until now, as for activity of PPAR δ, it is disclosed that hNUC1B (PPAR subtype whose structure is different from that of human NUC1 in one amino acid) inhibited the transcription activities of human PPAR α and thyroid hormone receptor (see WO9604130). Recently, it was reported that the compounds, which possessed high affinity to PPAR δ protein and which could activate PPAR δ significantly (i.e. agonists) were found out and that they had HDL (high density lipoprotein) cholesterol level-elevating activity and non-HDL cholesterol level-lowering effect (see WO9728149, WO0100603, Proc. Natl. Acad. Sci. USA., 98, 5306 (2001)). It turned out that macrophages introduced oxidized LDL, their foam occurred and they deposited into vascular endothelium to cause lipid metabolic disease. Therefore, agonists that can activate PPAR δ reduce foam cells by HDL cholesterol level-elevating effect and LDL cholesterol level-lowering effect and so they are expected to be useful for preventive and/or therapeutic agent of lipid metabolic disorder (e.g. hyperlipidemia (hypercholesterolemia, hypo-HDL-cholesterolemia, hyper-LDL-cholesterolemia, hypertriglyceridemia etc.), atherosclerosis, cardiovascular disease, adiposity, metabolic syndrome etc.), hypertension, circulatory diseases etc.
Recently, it was reported that activation of PPAR δ increased fatty acid oxidation in especially skeletal muscles (see Proc. Natl. Acad. Sci. USA., 100, 15924 (2003)). This also suggests that PPAR δ agonists are useful for the improvement of lipid metabolic disorder and therapy of adiposity.
The activation of PPAR δ doesn't only have the effect on lipid metabolic disorder, but also promote the cell differentiation of keratinocytes and is involved in sustain of skin structure as barrier function of organisms. It is observed that the over-proliferative changes of skins occur in PPAR δ-deficient mice treated with TPA (12-O-tetradecanoylphorbol-13-acetate) (see Mol. Cell. Biol., 20, 5119 (2000)). In addition, it is shown that it has the anti-inflammatory activity on dermal inflammation (see J. Invest. Dermatol., 122, 971 (2004)). Therefore, PPAR δ agonists are useful for the preventive and/or therapeutic agent of dermal inflammatory disease (e.g. dermatitis (atopic dermatitis etc.), erythralgia, pruritus etc.) and are expected to have the effect as therapeutic facilitated drug of wound (e.g. burn wound, external wound etc.). Additionally, it is observed that callosal myelin coating disorder occurs in PPAR δ-deficient mice (see Mol. Cell. Biol., 20, 5119 (2000)) and PPAR δ agonists have possibility of having utility as preventive and/or therapeutic agent of a certain nerve disease.
However, it was reported that certain drugs among PPAR γ agonists had hepatopathy and they required careful use as medicine. In addition, it is speculated that hepatotoxicity of side effect derives from thiazolidine structure, but there are no reports which any structure of compounds concretely avoids hepatotoxicity. It is very useful that they search structure able to avoiding toxicity on developing PPAR agonists.
In contrast, the compounds represented by formula (A)
(wherein A1A is C1-4 alkylene etc.; A2A is —O—; A3A is CH etc.; nA is 1 to 5; R1A is a halogen atom, trihalomethyl, trihalomethoxy etc.; R2A is C1-4 alkyl, trihalomethyl etc.; Cyc1A is 1,3-thiazolilene, 1,3-oxazolilene etc.; Cyc2A is carbocyclic ring, heterocyclic ring etc.; R3A is a hydrogen atom, C1-8 alkyl etc.; R4A is -A4A—CR8AR9A—COOR7A (wherein A4A is a single bond; R7A, R8A, R9A is a hydrogen atom, C1-4 alkyl) etc.) are known to be useful as PPAR regulator (see WO9946232).